The present invention relates to substituted thienopyrimidine compounds of general formula (I) as described and defined herein, to methods of preparing said compounds, to intermediate compounds useful for preparing said compounds, to pharmaceutical compositions and combinations comprising said compounds and to the use of said compounds for manufacturing a pharmaceutical composition for the treatment or prophylaxis of a disease, in particular of a hyper-proliferative and/or angiogenesis disorder, as a sole agent or in combination with other active ingredients.

BACKGROUND OF THE INVENTION

The present invention relates to chemical compounds that inhibit MKNK1 kinase (also known as MAP Kinase interacting Kinase, Mnk1) and/or MKNK2 kinase (also known as MAP Kinase interacting Kinase, Mnk2). Human MKNKs comprise a group of four proteins encoded by two genes (Gene symbols: MKNK1 and MKNK2) by alternative splicing. The b-forms lack a MAP kinase-binding domain situated at the C-terminus. The catalytic domains of the MKNK1 and MKNK2 are very similar and contain a unique DFD (Asp-Phe-Asp) motif in subdomain VII, which usually is DFG (Asp-Phe-Gly) in other protein kinases and suggested to alter ATP binding [Jauch et al., Structure 13, 1559-1568, 2005 and Jauch et al., EMBO J25, 4020-4032, 2006]. MKNK1a binds to and is activated by ERK and p38 MAP Kinases, but not by JNK1. MKNK2a binds to and is activated only by ERK. MKNK1b has low activity under all conditions and MKNK2b has a basal activity independent of ERK or p38 MAP Kinase. [Buxade M et al., Frontiers in Bioscience 5359-5374, May 1, 2008]

MKNKs have been shown to phosphorylate eukaryotic initiation factor 4E (eIF4E), heterogeneous nuclear RNA-binding protein A1 (hnRNP A1), polypyrimidine-tract binding protein-associated splicing factor (PSF), cytoplasmic phospholipase A2 (cPLA2) and Sprouty 2 (hSPRY2) [Buxade M et al., Frontiers in Bioscience 5359-5374, May 1, 2008].

eIF4E is an oncogene that is amplified in many cancers and is phosphorylated exclusively by MKNKs proteins as shown by KO-mouse studies [Konicek et al., Cell Cycle 7:16, 2466-2471, 2008; Ueda et al., Mol Cell Biol 24, 6539-6549, 2004]. eIF4E has a pivotal role in enabling the translation of cellular mRNAs. eIF4E binds the 7-methylguanosine cap at the 5â€² end of cellular mRNAs and delivers them to the ribosome as part of the eIF4F complex, also containing eIF4G and eIF4A. Though all capped mRNAs require eIF4E for translation, a pool of mRNAs is exceptionally dependent on elevated eIF4E activity for translation. These so-called â€œweak mRNAsâ€ are usually less efficiently translated due to their long and complex 5â€²UTR region and they encode proteins that play significant roles in all aspects of malignancy including VEGF, FGF-2, c-Myc, cyclin D1, survivin, BCL-2, MCL-1, MMP-9, heparanase, etc. Expression and function of eIF4E is elevated in multiple human cancers and directly related to disease progression [Konicek et al., Cell Cycle 7:16, 2466-2471, 2008].

MKNK1 and MKNK2 are the only kinases known to phosphorylate eIF4E at Ser209. Overall translation rates are not affected by eIF4E phosphorylation, but it has been suggested that eIF4E phosphorylation contributes to polysome formation (i.e. multiple ribosome on a single mRNA) that ultimately enables more efficient translation of â€œweak mRNAsâ€ [Buxade M et al., Frontiers in Bioscience 5359-5374, May 1, 2008]. Alternatively, phosphorylation of eIF4E by MKNK proteins might facilitate eIF4E release from the 5â€² cap so that the 48S complex can move along the â€œweak mRNAâ€ in order to locate the start codon [Blagden S P and Willis A E, Nat Rev Clin Oncol. 8(5):280-91, 2011]. Accordingly, increased eIF4E phosphorylation predicts poor prognosis in non-small cell lung cancer patients [Yoshizawa et al., Clin Cancer Res. 16(1):240-8, 2010]. Further data point to a functional role of MKNK1 in carcinogenesis, as overexpression of constitutively active MKNK1, but not of kinase-dead MKNK1, in mouse embryo fibroblasts accelerates tumor formation [Chrestensen C. A. et al., Genes Cells 12, 1133-1140, 2007]. Moreover, increased phosphorylation and activity of MKNK proteins correlate with overexpression of HER2 in breast cancer [Chrestensen, C. A. et al., J. Biol. Chem. 282, 4243-4252, 2007]. Constitutively active, but not kinase-dead, MKNK1 also accelerated tumor growth in a model using EÎ¼-Myc transgenic hematopoietic stem cells to produce tumors in mice. Comparable results were achieved when an eIF4E carrying a S209D mutation was analyzed. The 5209D mutation mimicks a phosphorylation at the MKNK1 phosphorylation site. In contrast, a non-phosphorylatable form of eIF4E attenuated tumor growth [Wendel H G, et al., Genes Dev. 21(24):3232-7, 2007]. A selective MKNK inhibitor that blocks eIF4E phosphorylation induces apoptosis and suppresses proliferation and soft agar growth of cancer cells in vitro. This inhibitor also suppresses outgrowth of experimental B16 melanoma pulmonary metastases and growth of subcutaneous HCT116 colon carcinoma xenograft tumors without affecting body weight [Konicek et al., Cancer Res. 71(5):1849-57, 2011]. In summary, eIF4E phosphorylation through MKNK protein activity can promote cellular proliferation and survival and is critical for malignant transformation. Inhibition of MKNK activity may provide a tractable cancer therapeutic approach.

Substituted thienopyrimidine compounds have been disclosed in prior art for the treatment or prophylaxis of different diseases:

WO 2010/006032 A1 (Duquesne University of the Holy Spirit) addresses tricyclic compounds as antimitotic agents. According to the general formula of claim 1, the tricycles inter alia comprise 5,6,7,8-tetrahydrobenzo[1]thieno[2,3-d]pyrimidines that may carry substituents at the carbocycle and one aromatic or heteroaromatic moiety at an optional 4-amino group. Furthermore, they may be unsubstituted at position 2 in the pyrimidine ring. However, the examples provided clearly differ from the compounds of the present invention. While the vast majority contains the C6 carbocycle completely unsaturated as aromatic ring, only two examples show a tetrahydrobenzo substructure in combination with a 4-amino group and in both cases the latter is bisubstituted by a phenyl and a methyl group. Furthermore, the specified compounds are with no exception pyrimidin-2-amines or 2-methyl-pyrimidines.

JP2007084494 (Oncorex Inc.) relates to PIM-1 inhibitors. One claim comprises 5,6,7,8-tetrahydrobenzo[1]thieno[2,3-d]pyrimidin-4-amines that can be monosubstituted at the amino group by optionally substituted phenyl. However, the optional substituents of phenyl are restricted to hydroxy, alkoxy or alkenyloxy. The tricyclic core does not show further substitutions. The only example of a direct substitution at the 4-amino group by phenyl is compound VII-2 with meta-methoxyphenyl.

WO 2002/088138 A1 (Bayer Pharmaceuticals Corporation) relates to PDE7b inhibitors and comprises 5,6,7,8-tetrahydrobenzo[l]thieno[2,3-d]pyrimidin-4-amines where the carbocycle and the 4-amino group may be optionally substituted by a wide range of substituents. The respective oxa, thia or aza analoga at position 7 with no further substituents at that ring are also claimed, the sulphur may be oxidized to sulphone and the nitrogen can be substituted. However, pyrid-4-yl in the 5,6,7,8-tetrahydrobenzo series and 3,4-dichlorophenyl and indazol-5-yl in the 6,9-dihydro-7H-pyrano series are the only examples with direct aromatic substitution at the 4-amino group.

WO 2005/010008 A1 (Bayer Pharmaceuticals Corporation) discloses 5,6,7,8-tetrahydrobenzo[1]thieno[2,3-d]pyrimidin-4-amines as proliferation inhibitors of A431 and BT474 cells which are model cell lines used in biomedical research. More specifically, A431 and BT474 cells are used in studies of the cell cycle and cancer-associated cell signalling pathways since they express abnormally high levels of the epidermal growth factor receptor (EGFR) and HER2, respectively. Substitution at the 4-amino group is limited to monosubstitution by either optionally substituted phenyl or optionally substituted indazolyl. The carbocycle may be substituted one or two times at position 7 by optionally substituted alkyl or alkenyl, by substituted carbonyl, hydroxy, optionally substituted amino or may be linked to the nitrogen of one or two saturated six membered rings optionally bearing a second heteroatom. Regarding the aromatic substituents at the 4-amino group, disclosed examples cover phenyl with a broad range of substituents and some indazol-5-yls but all are substituted at the nitrogen at position 1. Furthermore, all examples show an alkyl group in position 7 that is terminally further substituted by an amino group or hydroxyl group or in case of synthetic intermediates also by an ester function. Furthermore, as shown hereinafter, the compounds disclosed in WO 2005/010008 A1 are potent EGFR inhibitors but less effective MKNK inhibitors whereas the compounds of the present invention are potent MKNK inhibitors and less effective EGFR inhibitors. WO 2009/134658 (National Health Research Institutes) relates to inhibitors of Aurora kinase. The patent application generically covers tricyclic thieno[2,3-d]pyrimidin-4-amines with the third ring fused to the thiophene subunit. However, an optional aryl or heteroaryl substituent at the 4-amino group must carry a side chain involving a carbonyl, thiocarbonyl or iminomethylene group. The vast majority of more than 250 examples is formed by bicyclic 6,7-dihydrofuro[3,2-d]pyrimidin-4-amines that show in 4 cases a direct aromatic substitution at the 4-amino group but additionally substitution by two phenyl groups at the dihydrofuro subunit. None of the very few examples for tricyclic compounds shows direct substitution by an aromatic moiety at the 4-amino group.

WO 2006/136402 A1 and WO 2007/059905 A2 (Develogen AG) disclose thienopyrimidin-4-amines and their use for the prophylaxis and/or treatment of diseases which can be influenced by the inhibition of the kinase activity of Mnk1 and/or Mnk2. The 4-amino-group is substituted by a substituted phenyl group. The WO publications do not disclose any biological data.

WO 2010/023181 A1, WO 2011/104334 A1, WO 2011/104337 A1, WO 2011/104338 A1 and WO 2011/104340 A1 (Boehringer Ingelheim) relate to thienopyrimidin-4-amines for the prophylaxis and/or treatment of diseases which can be influenced by the inhibition of the kinase activity of Mnk1 and/or Mnk2. In case of the disclosed thienopyrimidin-4-amines there is no tetrahydrobenzo ring fused to the thienopyrimidine core. Additionally, the 4-amino group does not carry an indazol-5-yl substituent. In case of the compounds disclosed in WO 2010/023181 A1 the IC₅₀values vary between 0.035 Î¼M and 0.68 Î¼M with respect Mnk1, and between 0.006 Î¼M and 0.56 Î¼M with respect to Mnk2. In case of the compounds disclosed in WO 2011/104334 A1 the IC₅₀values vary between 1 nM and 9700 nM with respect to Mnk2. In case of the compounds disclosed in WO 2011/104337 A1 the IC₅₀values vary between 2 nM and 8417 nM with respect to Mnk2. In case of the compounds disclosed in WO 2011/104338 A1 the IC₅₀values vary between 8 nM and 58 nM with respect to Mnk2. In case of the compounds disclosed in WO 2011/104340 A1 the IC₅₀values vary between 3 nM and 5403 nM with respect to Mnk2. ALL WO publications contain the statement that the compounds described therein show improved solubility, are highly selective and show improved metabolic stability when compared to the compounds disclosed in WO 2006/136402 A1 and WO 2007/059905 A2 (Develogen AG, see above). However, besides the IC₅₀values discussed in this paragraph, there are no more data proving this statement.

The state of the art described above does not describe the specific substituted thienopyrimidine compounds of general formula (I) of the present invention as defined herein or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same, as described and defined herein, and as hereinafter referred to as â€œcompounds of the present inventionâ€ , or their pharmacological activity.

It has now been found, and this constitutes the basis of the present invention, that said compounds of the present invention have surprising and advantageous properties.

In particular, said compounds of the present invention have surprisingly been found to effectively inhibit MKNK1 kinase and may therefore be used for the treatment or prophylaxis of diseases of uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune responses, or inappropriate cellular inflammatory responses or diseases which are accompanied with uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune responses, or inappropriate cellular inflammatory responses, particularly in which the uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune responses, or inappropriate cellular inflammatory responses is mediated by MKNK1 kinase, such as, for example, haematological tumours, solid tumours, and/or metastases thereof, e.g. Leukaemias and myelodysplastic syndrome, malignant lymphomas, head and neck tumours including brain tumours and brain metastases, tumours of the thorax including non-small cell and small cell lung tumours, gastrointestinal tumours, endocrine tumours, mammary and other gynaecological tumours, urological tumours including renal, bladder and prostate tumours, skin tumours, and sarcomas, and/or metastases thereof.

Additionally, the compounds of the present invention show higher kinase inhibition selectivity and/or better performance in cellular assays than the MKNK inhibitors disclosed in prior art.

SUMMARY OF THE INVENTION

The present invention covers compounds of general formula (I):

[Image Omitted]

in which:

R¹represents a group selected from:
- â€”C(â• O)Oâ€”R³, â€”C(â• O)N(H)R³, â€”C(â• O)NR³R⁴;
R^2a, R^2b, R^2c, R^2d
- represent, independently from each other, a hydrogen atom or a group selected from C₁-C₃-alkyl-, C₁-C₃-alkoxy-, halo-, hydroxy-, halo-C₁-C₃-alkyl-, halo-C₁-C₃-alkoxy-, cyano-, â€”N(H)R⁵, â€”NR⁵R⁴;
R³represents a hydrogen atom or an optionally substituted group selected from:
- C₁-C₆-alkyl-, C₂-C₆-alkenyl-, C₂-C₆-alkynyl-, â€”(CH₂)_qâ€”(C₃-C₇-cycloalkyl), â€”(CH₂)_qâ€”Oâ€”(C₃-C₇-cycloalkyl), â€”(CH₂)_qâ€”(C₄-C₇-cycloalkenyl), â€”(CH₂)_qâ€”Oâ€”(C₄-C₇-cycloalkenyl), â€”(CH₂)_q-(3- to 10-membered heterocycloalkyl), â€”(CH₂)_qâ€”O-(3- to 10-membered heterocycoalkyl), â€”(CH₂)_q-(4- to 10-membered heterocycloalkenyl), â€”(CH₂)_qâ€”O-(4- to 10-membered heterocycloalkenyl),
- â€”(CH₂)_q-aryl, â€”(CH₂)_qâ€”O-aryl, â€”(CH₂)_q-heteroaryl, â€”(CH₂)_qâ€”O-heteroaryl,
R⁴represents an optionally substituted group selected from:
- C₁-C₆-alkyl-, C₂-C₆-alkenyl-, C₂-C₆-alkynyl-, halo-C₁-C₆-alkyl-, hydroxy-C₁-C₆-alkyl-, C₁-C₆-alkoxy-C₁-C₆-alkyl-;
or
NR³R⁴together
- represent an optionally substituted 3- to 10-membered heterocycloalkyl or an optionally substituted 4- to 10-membered heterocycloalkenyl group;
R⁵represents a hydrogen atom, a C₁-C₆-alkyl- or a C₃-C₇-cycloalkyl-group;
q represents an integer of 0, 1, 2 or 3;
or a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.

The present invention further relates to methods of preparing compounds of general formula (I), to pharmaceutical compositions and combinations comprising said compounds, to the use of said compounds for manufacturing a pharmaceutical composition for the treatment or prophylaxis of a disease, as well as to intermediate compounds useful in the preparation of said compounds.

DETAILED DESCRIPTION OF THE INVENTION

The terms as mentioned in the present text have preferably the following meanings:

The term â€œhalogen atomâ€ , â€œhalo-â€ or â€œHal-â€ is to be understood as meaning a fluorine, chlorine, bromine or iodine atom, preferably a fluorine or a chlorine atom.

The term â€œC₁-C₆-alkylâ€ is to be understood as preferably meaning a linear or branched, saturated, monovalent hydrocarbon group having 1, 2, 3, 4, 5 or 6 carbon atoms, e.g. a methyl, ethyl, propyl, butyl, pentyl, hexyl, iso-propyl, iso-butyl, sec-butyl, tert-butyl, iso-pentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neo-pentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl, or 1,2-dimethylbutyl group, or an isomer thereof. Particularly, said group has 1, 2, 3 or 4 carbon atoms (â€œC₁-C₄-alkylâ€ ), e.g. a methyl, ethyl, propyl, butyl, iso-propyl, iso-butyl, sec-butyl, tert-butyl group, more particularly 1, 2 or 3 carbon atoms (â€œC₁-C₃-alkylâ€ ), e.g. a methyl, ethyl, n-propyl- or iso-propyl group.

The term â€œhalo-C₁-C₆-alkylâ€ is to be understood as preferably meaning a linear or branched, saturated, monovalent hydrocarbon group in which the term â€œC₁-C₆-alkylâ€ is defined supra, and in which one or more hydrogen atoms is replaced by a halogen atom, in identically or differently, i.e. one halogen atom being independent from another. Particularly, said halogen atom is F. Said halo-C₁-C₆-alkyl group is, for example, â€”CF₃, â€”CHF₂, â€”CH₂F, â€”CF₂CF₃, or â€”CH₂CF₃.

The term â€œC₁-C₆-alkoxyâ€ is to be understood as preferably meaning a linear or branched, saturated, monovalent, hydrocarbon group of formula â€”Oâ€”(C₁-C₆-alkyl), in which the term â€œC₁-C₆-alkylâ€ is defined supra, e.g. a methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, tert-butoxy, sec-butoxy, pentoxy, iso-pentoxy, or n-hexoxy group, or an isomer thereof.

The term â€œhalo-C₁-C₆-alkoxyâ€ is to be understood as preferably meaning a linear or branched, saturated, monovalent C₁-C₆-alkoxy group, as defined supra, in which one or more of the hydrogen atoms is replaced, in identically or differently, by a halogen atom. Particularly, said halogen atom is F. Said halo-C₁-C₆-alkoxy group is, for example, â€”OCF₃, â€”OCHF₂, â€”OCH₂F, â€”OCF₂CF₃, or â€”OCH₂CF₃.

The term â€œC₁-C₆-alkoxy-C₁-C₆-alkylâ€ is to be understood as preferably meaning a linear or branched, saturated, monovalent C₁-C₆-alkyl group, as defined supra, in which one or more of the hydrogen atoms is replaced, in identically or differently, by a C₁-C₆-alkoxy group, as defined supra, e.g. methoxyalkyl, ethoxyalkyl, propyloxyalkyl, iso-propoxyalkyl, butoxyalkyl, iso-butoxyalkyl, tert-butoxyalkyl, sec-butoxyalkyl, pentyloxyalkyl, iso-pentyloxyalkyl, hexyloxyalkyl group, or an isomer thereof.

The term â€œhalo-C₁-C₆-alkoxy-C₁-C₆-alkylâ€ is to be understood as preferably meaning a linear or branched, saturated, monovalent C₁-C₆-alkoxy-C₁-C₆-alkyl group, as defined supra, in which one or more of the hydrogen atoms is replaced, in identically or differently, by a halogen atom. Particularly, said halogen atom is F. Said halo-C₁-C₆-alkoxy-C₁-C₆-alkyl group is, for example, â€”CH₂CH₂OCF₃, â€”CH₂CH₂OCHF₂, â€”CH₂CH₂OCH₂F, â€”CH₂CH₂OCF₂CF₃, or â€”CH₂CH₂OCH₂CF₃.

The term â€œC₂-C₆-alkenylâ€ is to be understood as preferably meaning a linear or branched, monovalent hydrocarbon group, which contains one or more double bonds, and which has 2, 3, 4, 5 or 6 carbon atoms, particularly 2 or 3 carbon atoms (â€œC₂-C₃-alkenylâ€ ), it being understood that in the case in which said alkenyl group contains more than one double bond, then said double bonds may be isolated from, or conjugated with, each other. Said alkenyl group is, for example, a vinyl, allyl, (E)-2-methylvinyl, (Z)-2-methylvinyl, homoallyl, (E)-but-2-enyl, (Z)-but-2-enyl, (E)-but-1-enyl, (Z)-but-1-enyl, pent-4-enyl, (E)-pent-3-enyl, (Z)-pent-3-enyl, (E)-pent-2-enyl, (Z)-pent-2-enyl, (E)-pent-1-enyl, (Z)-pent-1-enyl, hex-5-enyl, (E)-hex-4-enyl, (Z)-hex-4-enyl, (E)-hex-3-enyl, (Z)-hex-3-enyl, (E)-hex-2-enyl, (Z)-hex-2-enyl, (E)-hex-1-enyl, (Z)-hex-1-enyl, iso-propenyl, 2-methylprop-2-enyl, 1-methylprop-2-enyl, 2-methylprop-1-enyl, (E)-1-methylprop-1-enyl, (Z)-1-methylprop-1-enyl, 3-methylbut-3-enyl, 2-methylbut-3-enyl, 1-methylbut-3-enyl, 3-methylbut-2-enyl, (E)-2-methylbut-2-enyl, (Z)-2-methylbut-2-enyl, (E)-1-methylbut-2-enyl, (Z)-1-methylbut-2-enyl, (E)-3-methylbut-1-enyl, (Z)-3-methylbut-1-enyl, (E)-2-methylbut-1-enyl, (Z)-2-methylbut-1-enyl, (E)-1-methylbut-1-enyl, (Z)-1-methylbut-1-enyl, 1,1-dimethylprop-2-enyl, 1-ethylprop-1-enyl, 1-propylvinyl, 1-isopropylvinyl, 4-methylpent-4-enyl, 3-methylpent-4-enyl, 2-methylpent-4-enyl, 1-methylpent-4-enyl, 4-methylpent-3-enyl, (E)-3-methylpent-3-enyl, (Z)-3-methylpent-3-enyl, (E)-2-methylpent-3-enyl, (Z)-2-methylpent-3-enyl, (E)-1-methylpent-3-enyl, (Z)-1-methylpent-3-enyl, (E)-4-methylpent-2-enyl, (Z)-4-methylpent-2-enyl, (E)-3-methylpent-2-enyl, (Z)-3-methylpent-2-enyl, (E)-2-methylpent-2-enyl, (Z)-2-methylpent-2-enyl, (E)-1-methylpent-2-enyl, (Z)-1-methylpent-2-enyl, (E)-4-methylpent-1-enyl, (Z)-4-methylpent-1-enyl, (E)-3-methylpent-1-enyl, (Z)-3-methylpent-1-enyl, (E)-2-methylpent-1-enyl, (Z)-2-methylpent-1-enyl, (E)-1-methylpent-1-enyl, (Z)-1-methylpent-1-enyl, 3-ethylbut-3-enyl, 2-ethylbut-3-enyl, 1-ethylbut-3-enyl, (E)-3-ethylbut-2-enyl, (Z)-3-ethylbut-2-enyl, (E)-2-ethylbut-2-enyl, (Z)-2-ethylbut-2-enyl, (E)-1-ethylbut-2-enyl, (Z)-1-ethylbut-2-enyl, (E)-3-ethylbut-1-enyl, (Z)-3-ethylbut-1-enyl, 2-ethylbut-1-enyl, (E)-1-ethylbut-1-enyl, (Z)-1-ethylbut-1-enyl, 2-propylprop-2-enyl, 1-propylprop-2-enyl, 2-isopropylprop-2-enyl, 1-isopropylprop-2-enyl, (E)-2-propylprop-1-enyl, (Z)-2-propylprop-1-enyl, (E)-1-propylprop-1-enyl, (Z)-1-propylprop-1-enyl, (E)-2-isopropylprop-1-enyl, (Z)-2-isopropylprop-1-enyl, (E)-1-isopropylprop-1-enyl, (Z)-1-isopropylprop-1-enyl, (E)-3,3-dimethylprop-1-enyl, (Z)-3,3-dimethylprop-1-enyl, 1-(1,1-dimethylethyl)ethenyl, buta-1,3-dienyl, penta-1,4-dienyl, hexa-1,5-dienyl, or methylhexadienyl group. Particularly, said group is vinyl or allyl.

The term â€œC₂-C₆-alkynylâ€ is to be understood as preferably meaning a linear or branched, monovalent hydrocarbon group which contains one or more triple bonds, and which contains 2, 3, 4, 5 or 6 carbon atoms, particularly 2 or 3 carbon atoms (â€œC₂-C₃-alkynylâ€ ). Said C₂-C₆-alkynyl group is, for example, ethynyl, prop-1-ynyl, prop-2-ynyl, but-1-ynyl, but-2-ynyl, but-3-ynyl, pent-1-ynyl, pent-2-ynyl, pent-3-ynyl, pent-4-ynyl, hex-1-ynyl, hex-2-ynyl, hex-3-ynyl, hex-4-ynyl, hex-5-ynyl, 1-methylprop-2-ynyl, 2-methylbut-3-ynyl, 1-methylbut-3-ynyl, 1-methylbut-2-ynyl, 3-methylbut-1-ynyl, 1-ethylprop-2-ynyl, 3-methylpent-4-ynyl, 2-methylpent-4-ynyl, 1-methylpent-4-ynyl, 2-methylpent-3-ynyl, 1-methylpent-3-ynyl, 4-methylpent-2-ynyl, 1-methylpent-2-ynyl, 4-methylpent-1-ynyl, 3-methylpent-1-ynyl, 2-ethylbut-3-ynyl, 1-ethylbut-3-ynyl, 1-ethylbut-2-ynyl, 1-propylprop-2-ynyl, 1-isopropylprop-2-ynyl, 2,2-dimethyl-but-3-ynyl, 1,1-dimethylbut-3-ynyl, 1,1-dimethylbut-2-ynyl, or 3,3-dimethyl-but-1-ynyl group. Particularly, said alkynyl group is ethynyl, prop-1-ynyl, or prop-2-ynyl.

The term â€œC₃-C₇-cycloalkylâ€ is to be understood as meaning a saturated, monovalent, monocyclic hydrocarbon ring which contains 3, 4, 5, 6 or 7 carbon atoms. Said C₃-C₇-cycloalkyl group is for example a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl ring. Particularly, said ring contains 3, 4, 5 or 6 carbon atoms (â€œC₃-C₆-cycloalkylâ€ ).

The term â€œC₄-C₇-cycloalkenylâ€ is to be understood as preferably meaning a monovalent, monocyclic hydrocarbon ring which contains 4, 5, 6 or 7 carbon atoms and one or two double bonds, in conjugation or not, as the size of said cycloalkenyl ring allows. Said C₄-C₇-cycloalkenyl group is for example a cyclobutenyl, cyclopentenyl, or cyclohexenyl group.

The term â€œ3- to 10-membered heterocycloalkylâ€ , is to be understood as meaning a saturated, monovalent, mono- or bicyclic hydrocarbon ring which contains 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms, and one or more heteroatom-containing groups selected from C(â• O), O, S, S(â• O), S(â• O)₂, NR^a, in which R^arepresents a hydrogen atom, or a C₁-C₆-alkyl-group or a C₃-C₇-cycloalkyl-group; it being possible for said heterocycloalkyl group to be attached to the rest of the molecule via any one of the carbon atoms or, if present, the nitrogen atom.

Particularly, said 3- to 10-membered heterocycloalkyl can contain 2, 3, 4, or 5 carbon atoms, and one or more of the above-mentioned heteroatom-containing groups (a â€œ3- to 6-membered heterocycloalkylâ€ ), more particularly said heterocycloalkyl can contain 4 or 5 carbon atoms, and one or more of the above-mentioned heteroatom-containing groups (a â€œ5- to 6-membered heterocycloalkylâ€ ).

Particularly, without being limited thereto, said heterocycloalkyl can be a 4-membered ring, such as an azetidinyl, oxetanyl, or a 5-membered ring, such as tetrahydrofuranyl, dioxolinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, or a 6-membered ring, such as tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, or trithianyl, or a 7-membered ring, such as a diazepanyl ring, for example.

The term â€œ4- to 10-membered heterocycloalkenylâ€ , is to be understood as meaning an unsaturated, monovalent, mono- or bicyclic hydrocarbon ring which contains 3, 4, 5, 6, 7, 8 or 9 carbon atoms, and one or more heteroatom-containing groups selected from C(â• O), O, S, S(â• O), S(â• O)₂, NR^a, in which R^arepresents a hydrogen atom or a C₁-C₆-alkyl-group; it being possible for said heterocycloalkenyl group to be attached to the rest of the molecule via any one of the carbon atoms or, if present, the nitrogen atom. Examples of said heterocycloalkenyl may contain one or more double bonds, e.g. 4H-pyranyl, 2H-pyranyl, 3H-diazirinyl, 2,5-dihydro-1H-pyrrolyl, [1,3]dioxolyl, 4H-[1,3,4]thiadiazinyl, 2,5-dihydrofuranyl, 2,3-dihydrofuranyl, 2,5-dihydrothiophenyl, 2,3-dihydrothiophenyl, 4,5-dihydrooxazolyl, or 4H-[1,4]thiazinyl group.

The term â€œarylâ€ is to be understood as preferably meaning a monovalent, aromatic or partially aromatic, mono-, or bi- or tricyclic hydrocarbon ring having 6, 7, 8, 9, 10, 11, 12, 13 or 14 carbon atoms (a â€œC₆-C₁₄-arylâ€ group), particularly a ring having 6 carbon atoms (a â€œC₆-arylâ€ group), e.g. a phenyl group; or a ring having 9 carbon atoms (a â€œC₉-arylâ€ group), e.g. an indanyl or indenyl group, or a ring having 10 carbon atoms (a â€œC₁₀-arylâ€ group), e.g. a tetralinyl, dihydronaphthyl, or naphthyl group, or a biphenyl group (a â€œC₁₂-arylâ€ group), or a ring having 13 carbon atoms, (a â€œC₁₃-arylâ€ group), e.g. a fluorenyl group, or a ring having 14 carbon atoms, (a â€œC₁₄-arylâ€ group), e.g. an anthracenyl group. Preferably, the aryl group is a phenyl group.

The term â€œheteroarylâ€ is understood as preferably meaning a monovalent, monocyclic-, bicyclic- or tricyclic aromatic ring system having 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 ring atoms (a â€œ5- to 14-membered heteroarylâ€ group), particularly 5 or 6 or 9 or 10 atoms, and which contains at least one heteroatom which may be identical or different, said heteroatom being such as oxygen, nitrogen or sulfur, and in addition in each case can be benzocondensed. Particularly, heteroaryl is selected from thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, thia-4H-pyrazolyl etc., and benzo derivatives thereof, such as, for example, benzofuranyl, benzothienyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, benzotriazolyl, indazolyl, indolyl, isoindolyl, etc.; or pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, etc., and benzo derivatives thereof, such as, for example, quinolinyl, quinazolinyl, isoquinolinyl, etc.; or azocinyl, indolizinyl, purinyl, etc., and benzo derivatives thereof; or cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthpyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, xanthenyl, or oxepinyl, etc.

In general, and unless otherwise mentioned, the heteroarylic or heteroarylenic radicals include all the possible isomeric forms thereof, e.g. the positional isomers thereof. Thus, for some illustrative non-restricting example, the term pyridyl includes pyridin-2-yl, pyridin-3-yl, and pyridin-4-yl; or the term thienyl includes thien-2-yl and thien-3-yl. Preferably, the heteroaryl group is a pyridinyl group.

The term â€œC₁-C₆â€ , as used throughout this text, e.g. in the context of the definition of â€œC₁-C₆-alkylâ€ , â€œC₁-C₆-haloalkylâ€ , â€œC₁-C₆-alkoxyâ€ , or â€œC₁-C₆-haloalkoxyâ€ is to be understood as meaning an alkyl group having a finite number of carbon atoms of 1 to 6, i.e. 1, 2, 3, 4, 5, or 6 carbon atoms. It is to be understood further that said term â€œC₁-C₆â€ is to be interpreted as any sub-range comprised therein, e.g. C₁-C₆, C₂-C₅, C₃-C₄, C₁-C₂, C₁-C₃, C₁-C₄, C₁-C₅; particularly C₁-C₂, C₁-C₃, C₁-C₄, C₁-C₅, C₁-C₆; more particularly C₁-C₄; in the case of â€œC₁-C₆-haloalkylâ€ or â€œC₁-C₆-haloalkoxyâ€ even more particularly C₁-C₂.

Similarly, as used herein, the term â€œC₂-C₆â€ , as used throughout this text, e.g. in the context of the definitions of â€œC₂-C₆-alkenylâ€ and â€œC₂-C₆-alkynylâ€ , is to be understood as meaning an alkenyl group or an alkynyl group having a finite number of carbon atoms of 2 to 6, i.e. 2, 3, 4, 5, or 6 carbon atoms. It is to be understood further that said term â€œC₂-C₆â€ is to be interpreted as any sub-range comprised therein, e.g. C₂-C₆, C₃-C₅, C₃-C₄, C₂-C₃, C₂-C₄, C₂-C₅; particularly C₂-C₃.

Further, as used herein, the term â€œC₃-C₇â€ , as used throughout this text, e.g. in the context of the definition of â€œC₃-C₇-cycloalkylâ€ , is to be understood as meaning a cycloalkyl group having a finite number of carbon atoms of 3 to 7, i.e. 3, 4, 5, 6 or 7 carbon atoms. It is to be understood further that said term â€œC₃-C₇â€ is to be interpreted as any sub-range comprised therein, e.g. C₃-C₆, C₄-C₅, C₃-C₅, C₃-C₄, C₄-C₆, C₅-C₇; particularly C₃-C₆.

The term â€œsubstitutedâ€ means that one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valency under the existing circumstances is not exceeded, and that the substitution results in a stable compound. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.

The term â€œoptionally substitutedâ€ means that the number of substituents can be zero. Unless otherwise indicated, optionally substituted groups may be substituted with as many optional substituents as can be accommodated by replacing a hydrogen atom with a non-hydrogen substituent on any available carbon or nitrogen atom. Commonly, the number of optional substituents (when present) ranges from 1 to 3.

Ring system substituent means a substituent attached to an aromatic or nonaromatic ring system which, for example, replaces an available hydrogen on the ring system.

As used herein, the term â€œone or moreâ€ , e.g. in the definition of the substituents of the compounds of the general formulae of the present invention, is understood as meaning â€œone, two, three, four or five, particularly one, two, three or four, more particularly one, two or three, even more particularly one or twoâ€ .

The invention also includes all suitable isotopic variations of a compound of the invention. An isotopic variation of a compound of the invention is defined as one in which at least one atom is replaced by an atom having the same atomic number but an atomic mass different from the atomic mass usually or predominantly found in nature. Examples of isotopes that can be incorporated into a compound of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulphur, fluorine, chlorine, bromine and iodine, such as ²H (deuterium), ³H (tritium), ¹¹C, ¹³C, ¹⁴C, ¹⁵N, ¹⁷O, ¹⁸O, ³²P, ³³P, ³³S, ³⁴S, ³⁵S, ³⁶S, ¹⁸F, ³⁶Cl, ⁸²Br, ¹²³I, ¹²⁴I, ¹²⁹I and ¹³¹I, respectively. Certain isotopic variations of a compound of the invention, for example, those in which one or more radioactive isotopes such as ³H or ¹⁴C are incorporated, are useful in drug and/or substrate tissue distribution studies. Tritiated and carbon-14, i.e., ¹⁴C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with isotopes such as deuterium may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements and hence may be preferred in some circumstances. Isotopic variations of a compound of the invention can generally be prepared by conventional procedures known by a person skilled in the art such as by the illustrative methods or by the preparations described in the examples hereafter using appropriate isotopic variations of suitable reagents.

The compounds of this invention may contain one or more asymmetric centre, depending upon the location and nature of the various substituents desired. Asymmetric carbon atoms may be present in the (R) or (S) configuration, resulting in racemic mixtures in the case of a single asymmetric centre, and diastereomeric mixtures in the case of multiple asymmetric centres. In certain instances, asymmetry may also be present due to restricted rotation about a given bond, for example, the central bond adjoining two substituted aromatic rings of the specified compounds.

The compounds of the present invention may contain sulphur atoms which are asymmetric, such as an asymmetric sulphoxide or sulphoximine group, of structure:

[Image Omitted]

for example,
in which * indicates atoms to which the rest of the molecule can be bound.

Substituents on a ring may also be present in either cis or trans form. It is intended that all such configurations (including enantiomers and diastereomers), are included within the scope of the present invention.

Preferred compounds are those which produce the more desirable biological activity. Separated, pure or partially purified isomers and stereoisomers or racemic or diastereomeric mixtures of the compounds of this invention are also included within the scope of the present invention. The purification and the separation of such materials can be accomplished by standard techniques known in the art.

The optical isomers can be obtained by resolution of the racemic mixtures according to conventional processes, for example, by the formation of diastereoisomeric salts using an optically active acid or base or formation of covalent diastereomers. Examples of appropriate acids are tartaric, diacetyltartaric, ditoluoyltartaric and camphorsulfonic acid. Mixtures of diastereoisomers can be separated into their individual diastereomers on the basis of their physical and/or chemical differences by methods known in the art, for example, by chromatography or fractional crystallisation. The optically active bases or acids are then liberated from the separated diastereomeric salts. A different process for separation of optical isomers involves the use of chiral chromatography (e.g., chiral HPLC columns), with or without conventional derivatisation, optimally chosen to maximise the separation of the enantiomers. Suitable chiral HPLC columns are manufactured by Daicel, e.g., Chiracel OD and Chiracel OJ among many others, all routinely selectable. Enzymatic separations, with or without derivatisation, are also useful. The optically active compounds of this invention can likewise be obtained by chiral syntheses utilizing optically active starting materials.

In order to limit different types of isomers from each other reference is made to IUPAC Rules Section E (Pure Appl Chem 45, 11-30, 1976).

The present invention includes all possible stereoisomers of the compounds of the present invention as single stereoisomers, or as any mixture of said stereoisomers, e.g. (R)- or (S)-isomers, or (E)- or (Z)-isomers, in any ratio. Isolation of a single stereoisomer, e.g. a single enantiomer or a single diastereomer, of a compound of the present invention may be achieved by any suitable state of the art method, such as chromatography, especially chiral chromatography, for example.

Further, the compounds of the present invention may exist as tautomers. For example, any compound of the present invention which contains a pyrazole moiety as a heteroaryl group for example can exist as a 1H tautomer, or a 2H tautomer, or even a mixture in any amount of the two tautomers, or a triazole moiety for example can exist as a 1H tautomer, a 2H tautomer, or a 4H tautomer, or even a mixture in any amount of said 1H, 2H and 4H tautomers, namely:

[Image Omitted]

The present invention includes all possible tautomers of the compounds of the present invention as single tautomers, or as any mixture of said tautomers, in any ratio.

Further, the compounds of the present invention can exist as N-oxides, which are defined in that at least one nitrogen of the compounds of the present invention is oxidised. The present invention includes all such possible N-oxides.

The present invention also relates to useful forms of the compounds as disclosed herein, such as metabolites, hydrates, solvates, prodrugs, salts, in particular pharmaceutically acceptable salts, and co-precipitates.

Where the plural form of the word compounds, salts, polymorphs, hydrates, solvates and the like, is used herein, this is taken to mean also a single compound, salt, polymorph, isomer, hydrate, solvate or the like.

By â€œstable compoundâ€ or â€œstable structureâ€ is meant a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.

The compounds of the present invention can exist as a hydrate, or as a solvate, wherein the compounds of the present invention contain polar solvents, in particular water, methanol or ethanol for example as structural element of the crystal lattice of the compounds. The amount of polar solvents, in particular water, may exist in a stoichiometric or non-stoichiometric ratio. In the case of stoichiometric solvates, e.g. a hydrate, hemi-, (semi-), mono-, sesqui-, di-, tri-, tetra-, penta- etc. solvates or hydrates, respectively, are possible. The present invention includes all such hydrates or solvates.

Further, the compounds of the present invention can exist in free form, e.g. as a free base, or as a free acid, or as a zwitterion, or can exist in the form of a salt. Said salt may be any salt, either an organic or inorganic addition salt, particularly any pharmaceutically acceptable organic or inorganic addition salt, customarily used in pharmacy.

The term â€œpharmaceutically acceptable saltâ€ refers to a relatively non-toxic, inorganic or organic acid addition salt of a compound of the present invention. For example, see S. M. Berge, et al. â€œPharmaceutical Salts,â€ J. Pharm. Sci. 1977, 66, 1-19.

A suitable pharmaceutically acceptable salt of the compounds of the present invention may be, for example, an acid-addition salt of a compound of the present invention bearing a nitrogen atom, in a chain or in a ring, for example, which is sufficiently basic, such as an acid-addition salt with an inorganic acid, such as hydrochloric, hydrobromic, hydroiodic, sulfuric, bisulfuric, phosphoric, or nitric acid, for example, or with an organic acid, such as formic, acetic, acetoacetic, pyruvic, trifluoroacetic, propionic, butyric, hexanoic, heptanoic, undecanoic, lauric, benzoic, salicylic, 2-(4-hydroxybenzoyl)-benzoic, camphoric, cinnamic, cyclopentanepropionic, digluconic, 3-hydroxy-2-naphthoic, nicotinic, pamoic, pectinic, persulfuric, 3-phenylpropionic, picric, pivalic, 2-hydroxyethanesulfonate, itaconic, sulfamic, trifluoromethanesulfonic, dodecylsulfuric, ethansulfonic, benzenesulfonic, para-toluenesulfonic, methansulfonic, 2-naphthalenesulfonic, naphthalinedisulfonic, camphorsulfonic acid, citric, tartaric, stearic, lactic, oxalic, malonic, succinic, malic, adipic, alginic, maleic, fumaric, D-gluconic, mandelic, ascorbic, glucoheptanoic, glycerophosphoric, aspartic, sulfosalicylic, hemisulfuric, or thiocyanic acid, for example.

Further, another suitably pharmaceutically acceptable salt of a compound of the present invention which is sufficiently acidic, is an alkali metal salt, for example a sodium or potassium salt, an alkaline earth metal salt, for example a calcium or magnesium salt, an ammonium salt or a salt with an organic base which affords a physiologically acceptable cation, for example a salt with N-methyl-glucamine, dimethyl-glucamine, ethyl-glucamine, lysine, dicyclohexylamine, 1,6-hexadiamine, ethanolamine, glucosamine, sarcosine, serinol, tris-hydroxy-methyl-aminomethane, aminopropandiol, sovak-base, 1-amino-2,3,4-butantriol. Additionally, basic nitrogen containing groups may be quaternised with such agents as lower alkyl halides such as methyl, ethyl, propyl, and butyl chlorides, bromides and iodides; dialkyl sulfates like dimethyl, diethyl, and dibutyl sulfate; and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and strearyl chlorides, bromides and iodides, aralkyl halides like benzyl and phenethyl bromides and others.

Those skilled in the art will further recognise that acid addition salts of the claimed compounds may be prepared by reaction of the compounds with the appropriate inorganic or organic acid via any of a number of known methods. Alternatively, alkali and alkaline earth metal salts of acidic compounds of the invention are prepared by reacting the compounds of the invention with the appropriate base via a variety of known methods.

The present invention includes all possible salts of the compounds of the present invention as single salts, or as any mixture of said salts, in any ratio.

As used herein, the term â€œin vivo hydrolysable esterâ€ is understood as meaning an in vivo hydrolysable ester of a compound of the present invention containing a carboxy or hydroxy group, for example, a pharmaceutically acceptable ester which is hydrolysed in the human or animal body to produce the parent acid or alcohol. Suitable pharmaceutically acceptable esters for carboxy include for example alkyl, cycloalkyl and optionally substituted phenylalkyl, in particular benzyl esters, C₁-C₆alkoxymethyl esters, e.g. methoxymethyl, C₁-C₆alkanoyloxymethyl esters, e.g. pivaloyloxymethyl, phthalidyl esters, C₃-C₈cycloalkoxy-carbonyloxy-C₁-C₆alkyl esters, e.g. 1-cyclohexylcarbonyloxyethyl; 1,3-dioxolen-2-onylmethyl esters, e.g. 5-methyl-1,3-dioxolen-2-onylmethyl; and C₁-C₆-alkoxycarbonyloxyethyl esters, e.g. 1-methoxycarbonyloxyethyl, and may be formed at any carboxy group in the compounds of this invention.

An in vivo hydrolysable ester of a compound of the present invention containing a hydroxy group includes inorganic esters such as phosphate esters and [alpha]-acyloxyalkyl ethers and related compounds which as a result of the in vivo hydrolysis of the ester breakdown to give the parent hydroxy group. Examples of [alpha]-acyloxyalkyl ethers include acetoxymethoxy and 2,2-dimethylpropionyloxymethoxy. A selection of in vivo hydrolysable ester forming groups for hydroxy include alkanoyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl, alkoxycarbonyl (to give alkyl carbonate esters), dialkylcarbamoyl and N-(dialkylaminoethyl)-N-alkylcarbamoyl (to give carbamates), dialkylaminoacetyl and carboxyacetyl. The present invention covers all such esters.

Furthermore, the present invention includes all possible crystalline forms, or polymorphs, of the compounds of the present invention, either as single polymorphs, or as a mixture of more than one polymorphs, in any ratio.

In accordance with a first aspect, the present invention covers compounds of general formula (I):

[Image Omitted]

in which:

R¹represents a group selected from:
- â€”C(â• O)Oâ€”R³, â€”C(â• O)N(H)R³, â€”C(â• O)NR³R⁴;
R^2a, R^2b, R^2c, R^2d
- represent, independently from each other, a hydrogen atom or a group selected from: C₁-C₃-alkyl-, C₁-C₃-alkoxy-, halo-, hydroxy-, halo-C₁-C₃-alkyl-, halo-C₁-C₃-alkoxy-, cyano-, â€”N(H)R⁵, â€”NR⁵R⁴;
R³represents a hydrogen atom or a group selected from:
- C₁-C₆-alkyl-, C₂-C₆-alkenyl-, C₂-C₆-alkynyl-, â€”(CH₂)_qâ€”(C₃-C₇-cycloalkyl), â€”(CH₂)_qâ€”Oâ€”(C₃-C₇-cycloalkyl), â€”(CH₂)_qâ€”(C₄-C₇-cycloalkenyl), â€”(CH₂)_qâ€”Oâ€”(C₄-C₇-cycloalkenyl), â€”(CH₂)_q-(3- to 10-membered heterocycloalkyl), â€”(CH₂)_qâ€”O-(3- to 10-membered heterocycoalkyl), â€”(CH₂)_q-(4- to 10-membered heterocycloalkenyl), â€”(CH₂)_qâ€”O-(4- to 10-membered heterocycloalkenyl),
- â€”(CH₂)_q-aryl, â€”(CH₂)_qâ€”O-aryl, â€”(CH₂)_q-heteroaryl, â€”(CH₂)_qâ€”O-heteroaryl;
- wherein said selected group is optionally substituted;
R⁴represents a group selected from:
- C₁-C₆-alkyl-, C₂-C₆-alkenyl-, C₂-C₆-alkynyl-, halo-C₁-C₆-alkyl-, hydroxy-C₁-C₆-alkyl-, C₁-C₆-alkoxy-C₁-C₆-alkyl-;
- wherein said selected group is optionally substituted;
  or
NR³R⁴together
- represent an optionally substituted 3- to 10-membered heterocycloalkyl or an optionally substituted 4- to 10-membered heterocycloalkenyl group;
R⁵represents a hydrogen atom, a C₁-C₆-alkyl- or C₃-C₇-cycloalkyl-group;
q represents an integer of 0, 1, 2 or 3;
or a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.

In a preferred embodiment, the invention relates to compounds of formula (I), supra, wherein R¹represents â€”C(â• O)Oâ€”R³.

In another preferred embodiment, the invention relates to compounds of formula (I), supra, wherein R¹represents â€”C(â• O)N(H)R³.

In another preferred embodiment, the invention relates to compounds of formula (I), supra, wherein R¹represents â€”C(â• O)NR³R⁴.

In another preferred embodiment, the invention relates to compounds of formula (I), supra, wherein R^2arepresents a hydrogen atom.

In another preferred embodiment, the invention relates to compounds of formula (I), supra, wherein R^2brepresents a hydrogen atom or a group selected from: C₁-C₃-alkyl-, halo-C₁-C₃-alkyl-, cyano-.

In another preferred embodiment, the invention relates to compounds of formula (I), supra, wherein R^2brepresents a hydrogen atom or a C₁-C₃-alkyl-group.

In another preferred embodiment, the invention relates to compounds of formula (I), supra, wherein R^2brepresents a hydrogen atom.

In another preferred embodiment, the invention relates to compounds of formula (I), supra, wherein R^2crepresents a hydrogen atom or a group selected from: C₁-C₃-alkyl-, C₁-C₃-alkoxy-, halo-, â€”N(H)R⁵, â€”NR⁵R⁴.

In another preferred embodiment, the invention relates to compounds of formula (I), supra, wherein R^2crepresents a hydrogen atom or a C₁-C₃-alkyl-group.

In another preferred embodiment, the invention relates to compounds of formula (I), supra, wherein R^2crepresents a hydrogen atom.

In another preferred embodiment, the invention relates to compounds of formula (I), supra, wherein R^2drepresents a hydrogen atom or a group selected from: C₁-C₃-alkyl-, C₁-C₃-alkoxy-, halo-, â€”N(H)R⁵, â€”NR⁵R⁴.

In another preferred embodiment, the invention relates to compounds of formula (I), supra, wherein R^2drepresents a hydrogen atom or a group selected from: C₁-C₃-alkyl-, C₁-C₃-alkoxy-, halo-.

In another preferred embodiment, the invention relates to compounds of formula (I), supra, wherein R^2drepresents a C₁-C₃-alkoxy-group, preferably a methoxy-, ethoxy- or iso-propoxy-group.

In another preferred embodiment, the invention relates to compounds of formula (I), supra, wherein R^2drepresents a hydrogen atom or a C₁-C₃-alkoxy-group, preferably a methoxy-, ethoxy- or iso-propoxy-group.

In another preferred embodiment, the invention relates to compounds of formula (I), supra, wherein each of R^2a, R^2brepresents a hydrogen atom.

In another preferred embodiment, the invention relates to compounds of formula (I), supra, wherein each of R^2a, R^2b, and R^2crepresents a hydrogen atom.

In another preferred embodiment, the invention relates to compounds of formula (I), supra, wherein each of R^2a, R^2brepresents a hydrogen atom, R^2crepresents a hydrogen atom or a C₁-C₃-alkyl-group, and R^2ddoes not represent a hydrogen atom.

In another preferred embodiment, the invention relates to compounds of formula (I), supra, wherein each of R^2a, R^2b, and R^2crepresents a hydrogen atom, and R^2drepresents a hydrogen atom or a group selected from: C₁-C₃-alkoxy-, halo-.

In another preferred embodiment, the invention relates to compounds of formula (I), supra, wherein each of R^2a, R^2b, and R^2crepresents a hydrogen atom, and R^2drepresents a C₁-C₃-alkoxy-group, preferably a methoxy-, ethoxy- or iso-propoxy-group.

In another preferred embodiment, the invention relates to compounds of formula (I), supra, wherein each of R^2a, R^2b, R^2cand R^2drepresents a hydrogen atom.

In another preferred embodiment, the invention relates to compounds of formula (Ia):

[Image Omitted]

in which Q is selected from:

[Image Omitted]

wherein * indicates the point of attachment of said groups with the rest of the molecule.

In another preferred embodiment, the invention relates to compounds of formula (Ia):

[Image Omitted]

in which:
Q is selected from:

[Image Omitted]

wherein * indicates the point of attachment of said groups with the rest of the molecule.

In another preferred embodiment, the invention relates to compounds of formula (I), supra, wherein R³represents a hydrogen atom or a group selected from:

C₁-C₆-alkyl-, C₂-C₆-alkynyl-, C₃-C₇-cycloalkyl-,
â€”(CH₂)_qâ€”(C₃-C₇-cycloalkyl), â€”(CH₂)_qâ€”Oâ€”(C₃-C₇-cycloalkyl),
3- to 10-membered heterocycloalkyl,
â€”(CH₂)_q-(3- to 10-membered heterocycloalkyl),
â€”(CH₂)_qâ€”O-(3- to 10-membered heterocycoalkyl), aryl, â€”(CH₂)_q-aryl, â€”(CH₂)_qâ€”O-aryl, heteroaryl, â€”(CH₂)_q-heteroaryl, â€”(CH₂)_qâ€”O-heteroaryl;
said group being optionally substituted, one or more times, identically or differently, with a substituent selected from:
halo-, hydroxy-, oxo-(Oâ• ), cyano-, nitro-, C₁-C₆-alkyl-, C₂-C₆-alkenyl-, C₂-C₆-alkynyl-, halo-C₁-C₆-alkyl-, C₁-C₆-alkoxy-, halo-C₁-C₆-alkoxy-, hydroxy-C₁-C₆-alkyl, C₁-C₆-alkoxy-C₁-C₆-alkyl-, halo-C₁-C₆-alkoxy-C₁-C₆-alkyl-,
â€”(CH₂)_q-aryl, â€”(CH₂)_q-heteroaryl, â€”(CH₂)_qâ€”(C₃-C₇-cycloalkyl), â€”(CH₂)_q-(3- to 10-membered heterocycloalkyl),
R⁵â€”Oâ€”, â€”C(â• O)R⁵, â€”C(â• O)Oâ€”R⁵, â€”OC(â• O)â€”R⁵, â€”N(H)C(â• O)R⁵, â€”N(R⁴)C(â• O)R⁵, â€”N(H)C(â• O)NR⁵R⁴, â€”N(R⁴)C(â• O)NR⁵R⁴, â€”N(H)R⁵, â€”NR⁵R⁴, â€”C(â• O)N(H)R⁵, â€”C(â• O)NR⁵R⁴,
R⁴â€”Sâ€”, R⁴â€”S(â• O)â€”, R⁴â€”S(â• O)₂â€”, â€”N(H)S(â• O)R⁴, â€”N(R⁴)S(â• O)R⁴, â€”S(â• O)N(H)R⁵,
â€”S(â• O)NR⁵R⁴, â€”N(H)S(â• O)₂R⁴, â€”N(R⁴)S(â• O)₂R⁴, â€”S(â• O)₂N(H)R⁵, â€”S(â• O)₂NR⁵R⁴,

â€”S(â• O)(â• NR⁵)R⁴, â€”S(â• O)(â• NR⁴)R⁵, â€”Nâ• S(â• O)(R⁵)R⁴;

or
when two substituents are present ortho to each other on an aryl- or heteroaryl-ring, said two substituents together form a bridge:
*O(CH₂)_pO*, *NH(C(â• O))NH*, wherein * represent the point of attachment to said aryl- or heteroaryl-ring, wherein p is 1 or 2.

In another preferred embodiment, the invention relates to compounds of formula (I), supra, wherein R³represents a hydrogen atom or a group selected from:

C₁-C₆-alkyl-, C₂-C₆-alkenyl-, C₂-C₆-alkynyl-, C₃-C₇-cycloalkyl-,
â€”(CH₂)_qâ€”(C₃-C₇-cycloalkyl), â€”(CH₂)_qâ€”Oâ€”(C₃-C₇-cycloalkyl), C₄-C₇-cycloalkenyl-,
â€”(CH₂)_qâ€”(C₄-C₇-cycloalkenyl), â€”(CH₂)_qâ€”Oâ€”(C₄-C₇-cycloalkenyl),
3- to 10-membered heterocycloalkyl, â€”(CH₂)_q-(3- to 10-membered heterocycloalkyl), â€”(CH₂)_qâ€”O-(3- to 10-membered heterocycoalkyl),
4- to 10-membered heterocycloalkenyl, â€”(CH₂)_q-(4- to 10-membered heterocycloalkenyl), â€”(CH₂)_qâ€”O-(4- to 10-membered heterocycloalkenyl),
aryl, â€”(CH₂)_q-aryl, â€”(CH₂)_qâ€”O-aryl, heteroaryl, â€”(CH₂)_q-heteroaryl,
â€”(CH₂)_qâ€”O-heteroaryl;
said group being optionally substituted, one or more times, identically or differently, with a substituent selected from:
halo-, hydroxy-, oxo-(Oâ• ), cyano-, C₁-C₆-alkyl-, C₂-C₆-alkynyl-, halo-C₁-C₆-alkyl-, C₁-C₆-alkoxy-, â€”(CH₂)_q-aryl, â€”N(H)R⁵, â€”NR⁵R⁴, R⁴â€”S(â• O)₂â€”, â€”S(â• O)₂N(H)R⁵;
or
when two substituents are present ortho to each other on an aryl- or heteroaryl-ring, said two substituents together form a bridge:
*O(CH₂)_pO*, *NH(C(â• O))NH*, wherein * represent the point of attachment to said aryl- or heteroaryl-ring, wherein p is 1 or 2.

In another preferred embodiment, the invention relates to compounds of formula (I), supra, wherein R³represents a hydrogen atom or a group selected from:

C₁-C₆-alkyl-, C₃-C₇-cycloalkyl-, â€”(CH₂)_qâ€”(C₃-C₇-cycloalkyl), â€”(CH₂)_q-(3- to 10-membered heterocycloalkyl), â€”(CH₂)_q-aryl, â€”(CH₂)_q-heteroaryl;
said group being optionally substituted, one or more times, identically or differently, with a substituent selected from:
halo-, hydroxy-, cyano-, C₁-C₆-alkyl-, C₁-C₆-alkoxy-, â€”(CH₂)_q-aryl,
â€”N(H)R⁵, â€”NR⁵R⁴, â€”C(â• O)NR⁵R⁴, R⁴â€”S(â• O)₂â€”, â€”S(â• O)₂N(H)R⁵.

In another preferred embodiment, the invention relates to compounds of formula (I), supra, wherein R³represents a group selected from: aryl, â€”(CH₂)_q-aryl; said group being optionally substituted, one or more times, identically or differently, with a substituent selected from:

halo-, hydroxy-, cyano-, C₁-C₆-alkyl-, halo-C₁-C₆-alkyl-, C₁-C₆-alkoxy-, â€”N(H)R⁵, â€”NR⁵R⁴.

In another preferred embodiment, the invention relates to compounds of formula (I), supra, wherein R³represents a hydrogen atom or a group selected from:

C₁-C₆-alkyl-, â€”(CH₂)_qâ€”(C₃-C₇-cycloalkyl), â€”(CH₂)_q-aryl, â€”(CH₂)_qâ€”O-aryl,
â€”(CH₂)_q-heteroaryl;
said group being optionally substituted, one or more times, identically or differently, with a substituent selected from: halo-, hydroxy-, C₁-C₆-alkyl-,
halo-C₁-C₆-alkyl-, C₁-C₆-alkoxy-, â€”NR⁵R⁴, â€”S(â• O)₂N(H)R⁵;
or
when two substituents are present ortho to each other on an aryl- or heteroaryl-ring, said two substituents together form a bridge:
*O(CH₂)_pO*, wherein * represent the point of attachment to said aryl- or heteroaryl-ring, wherein p is 1 or 2.

In another preferred embodiment, the invention relates to compounds of formula (I), supra, wherein R³represents a hydrogen atom or a C₁-C₆-alkyl-group,

In another preferred embodiment, the invention relates to compounds of formula (I), supra, wherein NR³R⁴together represent a 3- to 10-membered heterocycloalkyl group; which is optionally substituted, one or more times, identically or differently, with halo-, hydroxyl-, cyano-, nitro-, C₁-C₆-alkyl-, halo-C₁-C₆-alkyl-, C₁-C₆-alkoxy-, halo-C₁-C₆-alkoxy-, hydroxy-C₁-C₆-alkyl-, C₁-C₆-alkoxy-C₁-C₆-alkyl-, R⁶R⁷Nâ€”C₁-C₆-alkyl-, halo-C₁-C₆-alkoxy-C₁-C₆-alkyl-, C₂-C₆-alkenyl-, C₂-C₆-alkynyl-, â€”(CH₂)_qâ€”C₃-C₇-cycloalkyl-, â€”(CH₂)_q-aryl, â€”(CH₂)_q-heteroaryl, â€”C(â• O)R⁵, â€”C(â• O)Oâ€”R⁵, â€”N(H)C(â• O)R⁵, R⁵â€”S(â• O)₂â€” or â€”C(â• O)NR⁶R⁷;

wherein said C₁-C₆-alkyl-, â€”(CH₂)_qâ€”C₃-C₇-cycloalkyl, â€”(CH₂)_q-aryl, or â€”(CH₂)_q-heteroaryl group is optionally substituted, one or more times, identically or differently, with a group selected from: cyano-, C₁-C₆-alkyl-, â€”NR⁶R⁷, â€”C(â• O)N(H)R⁵, â€”C(â• O)NR⁶R⁷.
R⁶represents a hydrogen atom, a C₁-C₆-alkyl- or a C₃-C₇-cycloalkyl-group, and R⁷represents a hydrogen atom, a C₁-C₆-alkyl- or a C₃-C₇-cycloalkyl-group; or NR⁶R⁷together represent a 3- to 10-membered heterocycloalkyl or a 4- to 10-membered heterocycloalkenyl group.

In another preferred embodiment, the invention relates to compounds of formula (I), supra, wherein NR³R⁴together represent a 3- to 10-membered heterocycloalkyl group; which is optionally substituted, one or more times, identically or differently, with hydroxyl, C₁-C₆-alkyl-, C₁-C₆-alkoxy-, hydroxy-C₁-C₆-alkyl-, C₁-C₆-alkoxy-C₁-C₆-alkyl-, â€”(CH₂)_qâ€”C₃-C₇-cycloalkyl, â€”(CH₂)_q-aryl, â€”(CH₂)_q-heteroaryl, â€”C(â• O)R⁵, â€”C(â• O)Oâ€”R⁵, â€”N(H)C(â• O)R⁵, R⁵â€”S(â• O)₂â€”, R⁶R⁷Nâ€”C₁-C₆-alkyl- or â€”C(â• O)NR⁶R⁷; wherein said C₁-C₆-alkyl-, â€”(CH₂)_qâ€”C₃-C₇-cycloalkyl, â€”(CH₂)_q-aryl, or â€”(CH₂)_q-heteroaryl group is optionally substituted, one or more times, identically or differently, with a group selected from: cyano-, C₁-C₆-alkyl-, â€”NR⁶R⁷, â€”C(â• O)N(H)R⁵, â€”C(â• O)NR⁶R⁷.

In another preferred embodiment, the invention relates to compounds of formula (I), supra, wherein NR³R⁴together represent a 3- to 10-membered heterocycloalkyl-group; which is optionally substituted, one or more times, identically or differently, with halo-, hydroxy-, C₁-C₆-alkyl-, halo-C₁-C₆-alkyl-, C₁-C₆-alkoxy-, halo-C₁-C₆-alkoxy-, hydroxy-C₁-C₆-alkyl-, C₁-C₆-alkoxy-C₁-C₆-alkyl-.

In another preferred embodiment, the invention relates to compounds of formula (I), supra, wherein NR³R⁴together represent a 3- to 10-membered heterocycloalkyl-group; said group being optionally substituted with C₁-C₃-alkyl-.

In another preferred embodiment, the invention relates to compounds of formula (I), supra, wherein R⁴represents a group selected from: C₁-C₆-alkyl-, halo-C₁-C₆-alkyl-, hydroxy-C₁-C₆-alkyl-.

In another preferred embodiment, the invention relates to compounds of formula (I), supra, wherein R⁴represents a group selected from: C₁-C₆-alkyl-, C₂-C₆-alkynyl-.

In another preferred embodiment, the invention relates to compounds of formula (I), supra, wherein R⁴represents a C₁-C₆-alkyl-group.

In another preferred embodiment, the invention relates to compounds of formula (I), supra, wherein R⁵represents a hydrogen atom, a C₁-C₆-alkyl- or C₃-C₇-cycloalkyl-group.

In another preferred embodiment, the invention relates to compounds of formula (I), supra, wherein R⁵represents a hydrogen atom or a C₁-C₆-alkyl-group.

In another preferred embodiment, the invention relates to compounds of formula (I), supra, wherein R⁵represents a C₁-C₆-alkyl-group.

In another preferred embodiment, the invention relates to compounds of formula (I), supra, wherein R⁵represents a hydrogen atom.

In another preferred embodiment, the invention relates to compounds of formula (I), supra, wherein R⁶represents a C₁-C₆-alkyl-group.

In another preferred embodiment, the invention relates to compounds of formula (I), supra, wherein R⁷represents a C₁-C₆-alkyl-group.

In another preferred embodiment, the invention relates to compounds of formula (I), supra, wherein NR⁶R⁷together represent a 3- to 10-membered heterocycloalkyl group.

In another preferred embodiment, the invention relates to compounds of formula (I), supra, wherein R⁵, R⁶and R⁷represent a C₁-C₆-alkyl-group.

In another preferred embodiment, the invention relates to compounds of formula (I), supra, wherein p represents 1.

In another preferred embodiment, the invention relates to compounds of formula (I), supra, wherein q represents 0.

In another preferred embodiment, the invention relates to compounds of formula (I), supra, wherein q represents 1.

In another preferred embodiment, the invention relates to compounds of formula (I), supra, wherein q represents 2.

In another preferred embodiment, the invention relates to compounds of formula (I), supra, wherein R¹is selected from:

[Image Omitted]

wherein * indicates the point of attachment of said groups with the rest of the molecule.

In a further embodiment of the above-mentioned aspect, the invention relates to compounds of formula (I), according to any of the above-mentioned embodiments, in the form of or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.

It is to be understood that the present invention relates also to any combination of the preferred embodiments described above.

Some examples of combinations are given hereinafter. However, the invention is not limited to these combinations.

In a preferred embodiment, the invention relates to compounds of formula (I):

[Image Omitted]

in which:

R¹represents a group selected from:
- â€”C(â• O)Oâ€”R³, â€”C(â• O)N(H)R³, â€”C(â• O)NR³R⁴;
R^2arepresents a hydrogen atom or a group selected from:
- C₁-C₃-alkyl-, C₁-C₃-alkoxy-, halo-, hydroxy-, halo-C₁-C₃-alkyl-,
- halo-C₁-C₃-alkoxy-, cyano-, â€”N(H)R⁵, â€”NR⁵R⁴;
R^2brepresents a hydrogen atom or a group selected from:
- C₁-C₃-alkyl-, C₁-C₃-alkoxy-, halo-, hydroxy-, halo-C₁-C₃-alkyl-,
- halo-C₁-C₃-alkoxy-, cyano-, â€”N(H)R⁵, â€”NR⁵R⁴;
R^2crepresents a hydrogen atom or a group selected from:
- C₁-C₃-alkyl-, C₁-C₃-alkoxy-, halo-, hydroxy-, halo-C₁-C₃-alkyl-,
- halo-C₁-C₃-alkoxy-, cyano-, â€”N(H)R⁵, â€”NR⁵R⁴;
R^2drepresents a hydrogen atom or a group selected from:
- C₁-C₃-alkyl-, C₁-C₃-alkoxy-, halo-, hydroxy-, halo-C₁-C₃-alkyl-, halo-C₁-C₃-alkoxy-, cyano-, â€”N(H)R⁵, â€”NR⁵R⁴;
R³represents a hydrogen atom or a group selected from:
- C₁-C₆-alkyl-, C₂-C₆-alkenyl-, C₂-C₆-alkynyl-, â€”(CH₂)_qâ€”(C₃-C₇-cycloalkyl), â€”(CH₂)_qâ€”Oâ€”(C₃-C₇-cycloalkyl), â€”(CH₂)_qâ€”(C₄-C₇-cycloalkenyl), â€”(CH₂)_qâ€”Oâ€”(C₄-C₇-cycloalkenyl), â€”(CH₂)_q-(3- to 10-membered heterocycloalkyl), â€”(CH₂)_qâ€”O-(3- to 10-membered heterocycoalkyl), â€”(CH₂)_q-(4- to 10-membered heterocycloalkenyl), â€”(CH₂)_qâ€”O-(4- to 10-membered heterocycloalkenyl),
- â€”(CH₂)_q-aryl, â€”(CH₂)_qâ€”O-aryl, â€”(CH₂)_q-heteroaryl, â€”(CH₂)_qâ€”O-heteroaryl;
- said group being optionally substituted, one or more times, identically or differently, with a substituent selected from:
- halo-, hydroxy-, oxo-(Oâ• ), cyano-, nitro-, C₁-C₆-alkyl-, C₂-C₆-alkenyl-, C₂-C₆-alkynyl-, halo-C₁-C₆-alkyl-, C₁-C₆-alkoxy-, halo-C₁-C₆-alkoxy-, hydroxy-C₁-C₆-alkyl-, C₁-C₆-alkoxy-C₁-C₆-alkyl-,
- â€”(CH₂)_q-aryl, â€”(CH₂)_q-heteroaryl, â€”(CH₂)_qâ€”(C₃-C₇-cycloalkyl), â€”(CH₂)_q-(3- to 10-membered heterocycloalkyl),
- halo-C₁-C₆-alkoxy-C₁-C₆-alkyl-, R⁵â€”Oâ€”, â€”C(â• O)R⁵, â€”C(â• O)Oâ€”R⁵, â€”OC(â• O)â€”R⁵, â€”N(H)C(â• O)R⁵, â€”N(R⁴)C(â• O)R⁵, â€”N(H)C(â• O)NR⁵R⁴, â€”N(R⁴)C(â• O)NR⁵R⁴, â€”N(H)R⁵, â€”NR⁵R⁴, â€”C(â• O)N(H)R⁵, â€”C(â• O)NR⁵R⁴, R⁴â€”Sâ€”, R⁴â€”S(â• O)â€”, R⁴â€”S(â• O)₂â€”,
- â€”N(H)S(â• O)R⁴, â€”N(R⁴)S(â• O)R⁴, â€”S(â• O)N(H)R⁵, â€”S(â• O)NR⁵R⁴,
- â€”N(H)S(â• O)₂R⁴, â€”N(R⁴)S(â• O)₂R⁴, â€”S(â• O)₂N(H)R⁵, â€”S(â• O)₂NR⁵R⁴,
- â€”S(â• O)(â• NR⁵)R⁴, â€”S(â• O)(â• NR⁴)R⁵, â€”Nâ• S(â• O)(R⁵)R⁴;
- or
- when two substituents are present ortho to each other on an aryl- or heteroaryl-ring, said two substituents together form a bridge:
- *O(CH₂)_pO*, *NH(C(â• O))NH*, wherein * represent the point of attachment to said aryl- or heteroaryl-ring;
R⁴represents a group selected from:
- C₁-C₆-alkyl-, C₂-C₆-alkenyl-, C₂-C₆-alkynyl-, halo-C₁-C₆-alkyl-, hydroxy-C₁-C₆-alkyl-, C₁-C₆-alkoxy-C₁-C₆-alkyl-;
or
NR³R⁴together
- represent a 3- to 10-membered heterocycloalkyl or 4- to 10-membered heterocycloalkenyl group;
- which is optionally substituted, one or more times, identically or differently, with halo-, hydroxy-, cyano-, nitro-, C₁-C₆-alkyl-, halo-C₁-C₆-alkyl-, C₁-C₆-alkoxy-, halo-C₁-C₆-alkoxy-, hydroxy-C₁-C₆-alkyl-, C₁-C₆-alkoxy-C₁-C₆-alkyl-, R⁶R⁷Nâ€”C₁-C₆-alkyl-, halo-C₁-C₆-alkoxy-C₁-C₆-alkyl-, C₂-C₆-alkenyl-, C₂-C₆-alkynyl-, â€”(CH₂)_qâ€”C₃-C₇-cycloalkyl, â€”(CH₂)_q-aryl, â€”(CH₂)_q-heteroaryl, R⁵â€”Oâ€”, â€”C(â• O)R⁵, â€”C(â• O)Oâ€”R⁵,
- â€”OC(â• O)â€”R⁵, â€”N(H)C(â• O)R⁵, â€”N(R⁴)C(â• O)R⁵, â€”N(H)C(â• O)NR⁶R⁷, â€”N(R⁵)C(â• O)NR⁶R⁷, â€”N(H)R⁵, â€”NR⁶R⁷, â€”C(â• O)N(H)R⁵, â€”C(â• O)NR⁶R⁷,
- R⁵â€”Sâ€”, R⁵â€”S(â• O)â€”, R⁵â€”S(â• O)₂â€”, â€”N(H)S(â• O)R⁵, â€”N(R⁵)S(â• O)R⁶,
- â€”S(â• O)N(H)R⁵, â€”S(â• O)NR⁶R⁷, â€”N(H)S(â• O)₂R⁵, â€”N(R⁵)S(â• O)₂R⁶, â€”S(â• O)₂N(H)R⁶,
- â€”S(â• O)₂NR⁶R⁷, â€”S(â• O)(â• NR⁵)R⁶, â€”S(â• O)(â• NR⁵)R⁶, â€”Nâ• S(â• O)(R⁵)R⁶;
- wherein said C₁-C₆-alkyl-, â€”(CH₂)_qâ€”C₃-C₇-cycloalkyl, â€”(CH₂)_q-aryl, or â€”(CH₂)_q-heteroaryl group is optionally substituted, one or more times, identically or differently, with a group selected from: halo-, hydroxy-, oxo-(Oâ• ), cyano-, nitro-, C₁-C₆-alkyl-, halo-C₁-C₆-alkyl-, C₁-C₆-alkoxy-, halo-C₁-C₆-alkoxy-, hydroxy-C₁-C₆-alkyl-, C₁-C₆-alkoxy-C₁-C₆-alkyl-, R⁶R⁷Nâ€”C₁-C₆-alkyl-, halo-C₁-C₆-alkoxy-C₁-C₆-alkyl-, C₂-C₆-alkenyl-, C₂-C₆-alkynyl-, R⁵â€”Oâ€”, â€”C(â• O)R⁵, â€”C(â• O)Oâ€”R⁵, â€”OC(â• O)â€”R⁵, â€”N(H)C(â• O)R⁵, â€”N(R⁴)C(â• O)R⁵, â€”N(H)C(â• O)NR⁶R⁷, â€”N(R⁵)C(â• O)NR⁶R⁷, â€”N(H)R⁵,
- â€”NR⁶R⁷, â€”C(â• O)N(H)R⁵, â€”C(â• O)NR⁶R⁷, R⁵â€”Sâ€”, R⁵â€”S(â• O)â€”, R⁵â€”S(â• O)₂â€”, â€”N(H)S(â• O)R⁵, â€”N(R⁵)S(â• O)R⁶, â€”S(â• O)N(H)R⁵, â€”S(â• O)NR⁵R⁶, â€”N(H)S(â• O)₂R⁵, â€”N(R⁵)S(â• O)₂R⁶, â€”S(â• O)₂N(H)R⁶, â€”S(â• O)₂NR⁵R⁶, â€”S(â• O)(â• NR⁵)R⁶, â€”S(â• O)(â• NR⁵)R⁶, â€”Nâ• S(â• O)(R⁵)R⁶;
R⁵represents a hydrogen atom, a C₁-C₆-alkyl- or a C₃-C₇-cycloalkyl-group;
R⁶represents a hydrogen atom, a C₁-C₆-alkyl- or a C₃-C₇-cycloalkyl-group;
R⁷represents a hydrogen atom, a C₁-C₆-alkyl- or a C₃-C₇-cycloalkyl-group;
or
NR⁶R⁷together represent a 3- to 10-membered heterocycloalkyl or a 4- to 10-membered heterocycloalkenyl group;
p represents an integer of 1 or 2;
q represents an integer of 0, 1, 2 or 3;
or a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.

In a preferred embodiment, the invention relates to compounds of formula (I):

[Image Omitted]

in which:

R¹represents a group selected from:
- â€”C(â• O)Oâ€”R³, â€”C(â• O)N(H)R³, â€”C(â• O)NR³R⁴;
R^2arepresents a hydrogen atom or a C₁-C₃-alkyl-group;
R^2brepresents a hydrogen atom or a group selected from:
- C₁-C₃-alkyl-, halo-C₁-C₃-alkyl-, cyano-;
R^2crepresents a hydrogen atom or a group selected from:
- C₁-C₃-alkyl-, C₁-C₃-alkoxy-, halo-, â€”N(H)R⁵, â€”NR⁵R⁴;
R^2drepresents a hydrogen atom or a group selected from:
- C₁-C₃-alkyl-, C₁-C₃-alkoxy-, halo-, â€”N(H)R⁵, â€”NR⁵R⁴;
R³represents a hydrogen atom or a group selected from:
- C₁-C₆-alkyl-, C₂-C₆-alkenyl-, C₂-C₆-alkynyl-,
- C₃-C₇-cycloalkyl-, â€”(CH₂)_qâ€”(C₃-C₇-cycloalkyl),
- â€”(CH₂)_qâ€”Oâ€”(C₃-C₇-cycloalkyl), C₄-C₇-cycloalkenyl-, â€”(CH₂)_qâ€”(C₄-C₇-cycloalkenyl), â€”(CH₂)_qâ€”Oâ€”(C₄-C₇-cycloalkenyl),
- 3- to 10-membered heterocycloalkyl, â€”(CH₂)_q-(3- to 10-membered heterocycloalkyl),
- â€”(CH₂)_qâ€”O-(3- to 10-membered heterocycoalkyl),
- 4- to 10-membered heterocycloalkenyl,
- â€”(CH₂)_q-(4- to 10-membered heterocycloalkenyl),
- â€”(CH₂)_qâ€”O-(4- to 10-membered heterocycloalkenyl),
- aryl, â€”(CH₂)_q-aryl, â€”(CH₂)_qâ€”O-aryl, heteroaryl,
- â€”(CH₂)_q-heteroaryl, â€”(CH₂)_qâ€”O-heteroaryl;
- said group being optionally substituted, one or more times, identically or differently, with a substituent selected from:
- halo-, hydroxy-, oxo-(Oâ• ), cyano-, nitro-, C₁-C₆-alkyl-, C₂-C₆-alkenyl-, C₂-C₆-alkynyl-, halo-C₁-C₆-alkyl-, C₁-C₆-alkoxy-, halo-C₁-C₆-alkoxy-, hydroxy-C₁-C₆-alkyl-, C₁-C₆-alkoxy-C₁-C₆-alkyl-,
- halo-C₁-C₆-alkoxy-C₁-C₆-alkyl-, R⁵â€”Oâ€”, â€”C(â• O)R⁵, â€”C(â• O)Oâ€”R⁵, â€”OC(â• O)â€”R⁵,
- â€”N(H)C(â• O)R⁵, â€”N(R⁴)C(â• O)R⁵, â€”N(H)C(â• O)NR⁵R⁴, â€”N(R⁴)C(â• O)NR⁵R⁴, â€”N(H)R⁵,
- â€”NR⁵R⁴, â€”C(â• O)N(H)R⁵, â€”C(â• O)NR⁵R⁴, R⁴â€”Sâ€”, R⁴â€”S(â• O)â€”, R⁴â€”S(â• O)₂â€”,
- â€”N(H)S(â• O)R⁴, â€”N(R⁴)S(â• O)R⁴, â€”S(â• O)N(H)R⁵, â€”S(â• O)NR⁵R⁴,
- â€”N(H)S(â• O)₂R⁴, â€”N(R⁴)S(â• O)₂R⁴, â€”S(â• O)₂N(H)R⁵, â€”S(â• O)₂NR⁵R⁴,
- â€”S(â• O)(â• NR⁵)R⁴, â€”S(â• O)(â• NR⁴)R⁵, â€”Nâ• S(â• O)(R⁵)R⁴;
- or
- when two substituents are present ortho to each other on an aryl- or heteroaryl-ring, said two substituents together form a bridge:
- *O(CH₂)_pO*, *NH(C(â• O))NH*, wherein * represent the point of attachment to said aryl- or heteroaryl-ring;
R⁴represents a C₁-C₆-alkyl- or hydroxy-C₁-C₆-alkyl-group;
or
NR³R⁴together
- represent a 3- to 10-membered heterocycloalkyl or a 4- to 10-membered heterocycloalkenyl group;
- which is optionally substituted, one or more times, identically or differently, with halo-, hydroxyl-, cyano-, nitro-, C₁-C₆-alkyl-, halo-C₁-C₆-alkyl-,
- C₁-C₆-alkoxy-, halo-C₁-C₆-alkoxy-, hydroxy-C₁-C₆-alkyl-, C₁-C₆-alkoxy-C₁-C₆-alkyl-, â€”NR⁶R⁷, R⁶R⁷Nâ€”C₁-C₆-alkyl-,
- halo-C₁-C₆-alkoxy-C₁-C₆-alkyl-, C₂-C₆-alkenyl-, C₂-C₆-alkynyl-,
- C₃-C₇-cycloalkyl- or â€”C(â• O)NR⁶R⁷;
R⁵represents a hydrogen atom, a C₁-C₆-alkyl- or a C₃-C₇-cycloalkyl-group;
R⁶represents a hydrogen atom, a C₁-C₆-alkyl- or a C₃-C₇-cycloalkyl-group;
R⁷represents a hydrogen atom, a C₁-C₆-alkyl- or a C₃-C₇-cycloalkyl-group;
or
NR⁶R⁷together represent a 3- to 10-membered heterocycloalkyl or 4- to 10-membered heterocycloalkenyl group;
p represents an integer of 1 or 2;
q represents an integer of 1, 2 or 3;
or a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.